Organic Chemistry III...Other Synthesis Reactions: いいね！1,513 Follow Synthesis of primary...

Organic Chemistry III

後藤 佑樹 (Yuki Goto, Bioorganic Chemistry Lab.)

担当日：6/6 (Wed) 6/13 (Wed) 6/20 (Wed) 6/27 (Wed) 7/4 (Wed)

“Organic chemistry of biomolecules”

“Organic chemistry of radicals”

1

Review of the previous class

Classification of monosaccharidealdoses/ketoses, pentoses/hexoses

How to understand/draw Fischer projections4 tips to draw and modify Fischer projections

D/L nomenclatureconvenient way to categorize stereochemistry of biomolecules

Cyclic forms of sugarshemiacetal formation, furanoses/pyranosesanomers, definition of α- and β-anomers

Reactions of monosaccharidessimple transformation of aldehydes (reduction and oxidation)simple transformation of alcohols (alkylation and acylation)

2

Q and A

3

Q and A

Formation of cyclic sugars via hemiacetal formation

(R)(S)

“Squiggle” indicates both stereoisomers are present (mixed)

D-glucopyranose

α-D-glucopyranose

β-D-glucopyranose

=

=

*

*

new chiral center!

If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.

*

*

63

37

：

Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).

“anomeric position”

“anomers”

56

Formation of cyclic sugars via hemiacetal formation

(R)(S)

“Squiggle” indicates both stereoisomers are present (mixed)

D-glucopyranose

α-D-glucopyranose

β-D-glucopyranose

=

=

*

*

new chiral center!

If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.

*

*

63

37

：

Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).

“anomeric position”

“anomers”

56

Formation of cyclic sugars via hemiacetal formation

(R)(S)

“Squiggle” indicates both stereoisomers are present (mixed)

D-glucopyranose

α-D-glucopyranose

β-D-glucopyranose

=

=

*

*

new chiral center!

If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.

*

*

63

37

：

Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).

“anomeric position”

“anomers”

56

OCHR2

OH

CH(OH)R

H

fix “OH” and rotate others

OCHR2

OHR(HO)HC

H

OCHR2

OHR(HO)HC

H 4

1

23

Formation of cyclic sugars via hemiacetal formation

(R)(S)

“Squiggle” indicates both stereoisomers are present (mixed)

D-glucopyranose

α-D-glucopyranose

β-D-glucopyranose

=

=

*

*

new chiral center!

If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.

*

*

63

37

：

Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).

“anomeric position”

“anomers”

564

絶対立体配置（R/S表記）の仕方まずは、練習として

の立体を絶対立体配置で表記しよう

(1) 置換基にランキングをつける。 (a) 原子番号の大きな原子が順位が高い。ここでは1が高くて4が低いとする。

★★

5

(S)

1C

423

1

2 3

(R)

1C

4 23

鏡

鏡

1

3 2

S鏡像異性体1→2→3 は反時計回り

R鏡像異性体1→2→3 は時計回り

(2) 順位が一番低い（4番）置換基を遠くにもっていく。

絶対立体配置（R/S表記）の仕方

(3) 手前側の三つの官能基の順位が右回りならR体左回りならS体

★★

(4) RとSは（）にいれてイタリックで。

6

絶対立体配置（R/S表記）の仕方まずは、練習として

の立体を絶対立体配置で表記しよう

★★

(S)

1C

423

1

2 3

(R)

1C

4 23

鏡

鏡

1

3 2

S鏡像異性体1→2→3 は反時計回り

R鏡像異性体1→2→3 は時計回り

RとSは（）にいれてイタリックで。(1) (2) (3) (4)

(S)-bromochlorofluoromethane

7

Q and A

8

Q and A

Sucrose!Sucrose is detected by our tongues more happily in the presence of triacylglycerols.

まじか。I am going to change the topic in the last class (or skip it).

9

Q and A

7/10（Wed）7/17（Wed）7/19（Fri）7/24（Wed）7/31（Wed）

candidate dates for final exam.

10

Amino acids

11

Topics

• structure of amino acids- classification and examples - acidity and basicity of amino acids

• synthesis of amino acids- amine synthesis

- side chain addition - COOH synthesis - enantioselective synthesis

• synthesis of amines- by SN2 reactions - Gabriel synthesis - reductive amination

12

What are amino acids

amine + acid

H2NOH

O

H2NOH

O

α-amino acids

γ-amino acids

(glycine)

(γ-amino butyric acid, GABA)

Proteinogenic amino acids are

α-amino acids (Fischer projection)

side chain (側鎖)

Review

H2NOH

O

R

13

What are amino acids

amine + acid

H2NOH

O

H2NOH

O

α-amino acids

γ-amino acids

(glycine)

(γ-amino butyric acid, GABA)

Proteinogenic amino acids are

L-α-amino acids

H2NOH

O

R

(Fischer projection)

side chain (側鎖)

Review

14

Examples/names of amino acids

Gly (G)

Ala (A)

Val (V)

Phe (F)

e.g.)

A total of 20 different amino acids is found in proteins. See others in the appendix.

15

acidity/basicity of amino acids

（双性イオン）

When the pH = pI (等電点: isoelectronic point), the net charge of amino acid becomes zero.

In this pH, the amino acid is mainly present as zwitterion.

Quiz pKa values of general carboxylic acids are 4~5. Why the pKa values of COOH in amino acids are unusually small?

Review Quiz Explain the aqueous structures of alanine in buffers of pH = 2.34, 6.00, and 9.69.

Quiz Estimate the pI values of Glu, His, and Tyr.

16

Topics

• structure of amino acids- classification and examples - acidity and basicity of amino acids

• synthesis of amino acids- amine synthesis

- side chain addition - COOH synthesis - enantioselective synthesis

• synthesis of amines- by SN2 reactions - Gabriel synthesis - reductive amination

17

Synthesis of amino acids-1 amine synthesisSN2 of α-halo acids with NH3

18

Synthesis of primary amines (general organic chemistry)

・SN2 of alkyl halides with NH3

RX

RNH2

R

HN

R+ NH3

RX

RN

R

R

R N R

R

R

RX

RX

pKaH: (R = Et)

9.21 10.63 10.98

10.75

19

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

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Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

Synthesis of primary amines (general organic chemistry)

・SN2 of alkyl halides with N3-

RX + NaN3 R

NH2R

N3R3P other reductants:

Pd/C & H2, LAH, etc.

・Gabriel synthesis

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us

Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us

Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us

Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us

Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us

Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com

1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis

Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us

Gabriel synthesis

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using

phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the

phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide

intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation

of the final primary amine product and phthalhydrazide by-product.[1]

References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Mechanism

Mechanism

Mechanism

Mechanism

1.

Other Synthesis Reactions:

いいね！ 1,513 Follow

+

isolatable, storable

(phosphine)

20

Synthesis of amines (general organic chemistry)

・Reductive amination（還元的アミノ化）

can be performed in one-pot often done in weak acidic cond.

Review Quiz Show the mechanism of imine formation and explain why reductive amination reactions are often performed in weak acidic conditions.

aldehydes can be also the SM.

21

Synthesis of amines (general organic chemistry)

22

Topics

• structure of amino acids- classification and examples - acidity and basicity of amino acids

• synthesis of amino acids- amine synthesis

- side chain addition - COOH synthesis - enantioselective synthesis

• synthesis of amines- by SN2 reactions - Gabriel synthesis - reductive amination

23

Synthesis of amino acids-2 side chain addition・Alkylation of acetamidomalonate

1. Base 2. R-X 3. H+, Δ

hydrolysis &

decarboxylation

1. Base 2. R-X 3. H+, Δ

Note; homologous to malonic ester synthesis see P.957 of Jones OC 5th Ed.

24

Synthesis of amino acids-3 COOH synthesis・Strecker synthesis

25

Reaction of monosaccharides - 3Elongation of chains in monosaccharides (Kiliani-Fischer synthesis)

“cyanohydrin”

partial hydrogenation

“imine”

Review quiz: Draw the mechanism of the hydrolysis of the imine under acidic conditions.

hydrolysis

cf.

26

Enantioseparation of amino acids・Formation of diastereomeric salts

D/L mixture

27

Enantioseparation of amino acids・Kinetic resolution

D/L mixture

28

(Advanced) Enantioselective synthesis of amino acids・Maruoka catalyst

Maruoka catalyst

29

What are amino acids

amine + acid

H2NOH

O

H2NOH

O

α-amino acids

γ-amino acids

(glycine)

(γ-amino butyric acid, GABA)

Proteinogenic amino acids are

L-α-amino acids

H2NOH

O

R

COOH

HH2N

Rside chain (側鎖)

(Fischer projection)Review

30

acidity/basicity of amino acids

（双性イオン）

Quiz pKa values of general carboxylic acids are 4~5. Why the pKa values of COOH in amino acids are unusually small?

Review Quiz Explain the aqueous structures of alanine in buffers of pH = 2.34, 6.00, and 9.69.

Quiz Estimate the pI values of Glu, His, and Tyr.

When the pH = pI (等電点: isoelectronic point), the net charge of amino acid becomes zero.

In this pH, the amino acid is mainly present as zwitterion.

31

Synthesis of amines (general organic chemistry)

・Reductive amination（還元的アミノ化）

can be performed in one-pot often done in weak acidic cond.

Review Quiz Show the mechanism of imine formation and explain why reductive amination reactions are often performed in weak acidic conditions.

aldehydes can be also the SM.

32

Synthesis of amines (general organic chemistry)

https://www.masterorganicchemistry.com

33